2, 4-di-(chlorosulfonyl)-anilidenes and their preparation



United States Patent 3,206,507 2,4-DI-(CHLOROSULFONYL)-ANILIDENES AND THEIR PREPARATION John G. Topliss, East Orange, Margaret H. Sherlock,

Bloomfield, and Nathan Sperber, North Caldwell, N.J., assignors to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey No Drawing. Filed Apr. 25, 1960, Ser. No. 24,262 8 Claims. (Cl. 260-543) This invention relates to a new process for the manufacture of therapeutically useful substances and to new and useful intermediates produced therein. More particularly, this invention relates to novel chlorosulfonyl anilidenes, their preparation and transformation into therapeutically useful 3,4-dihydro-l,2,4-benzothiadiaz.ine-1,1- dioxides.

According to our novel process, an aniline-2,4-disulfonyl chloride (I) is reacted with an aldehydic reactant such as aldehyde or a derivative convertible thereinto such as an acetal or a hydrate in the presence of a strong acid catalyst whereby a 2,4-di-(chlorosulfonyl)-anilidene (II) is produced. These anilidenes (II), when reacted with ammonia or a mono-substituted amine, preferably the former, undergo amination of the sulfonyl chloride groups and subsequent ring closure, thus forming the therapeutically useful 3,4-dihydro-1,2,4-benzothiadiazine- 1,1-dioxides (IV). The process employing ammonia and the novel compounds of this invention are illustrated in the following equation:

X NH: ECHO X =CH-R 0102s S0201 0101s S0201 In the foregoing scheme X represents halogeno such as chloro, bromo, fluoro, and trifiuoromethyl; and R represents alkyl having from 1 to 10 carbon atoms, haloalkyl having 1 to 5 carbon atoms in its alkyl portion of the radical and having up to three halogen substituents, aralkyl such as benzyl which may be aromatically substituted by halogen, alkyl or lower alkoxy and the like, monohomocyclic and heterocyclic aryl such as phenyl, and pyridyl which may contain further substituents such as alkyl and halogen; and benzylthioalkyl.

The condensation reaction is generally carried out at above room temperatures, preferably in the presence of a solvent.

When carried out in the absence of a solvent, the temperature range is from about C. to the boiling point of the aldehydic reactant, although the preferred range is from about 80 C to about 100 C. When the condensation reaction is carried out in the presence of a solvent the temperature is usually maintained at the reflux temperature of the mixture. The heating is usually continued for several hours until the reaction is complete, as may be indicated by a rise in temperature Within the reaction vessel. The concentration of the reactants may be in equal molar quantities, or an excess of the aldehydic compound may be used. While not a necessity to the mechanism of the condensation, it is preferable to effect the condensation in the presence of a strong acid catalyst, said catalyst being present in amounts up to about 0.03 mole per mole of disulfonyl chloride reactant, and also .to make provision for the removal of water formed by the reaction, preferably by azeoitropic techniques. If necessary, the reaction may be performed under increased pressure or in the atmosphere of an inert gas, e.g., nitrogen. In instances wherein an acetal is a reactant, it is advantageous to initially add a small catalytic quantity of Water to the system.

The amination and cyclization of the condensation products to form the therapeutically valuable 3,4-dihydro- 1,2,4-benzothiadiazine-1,l-dioxides is effected with the use of ammonia (II- IV). The reaction is preferably carried out using an excess of liquid ammonia in quantities wherein the ammonia itself may behave as the reaction solvent. Ammonia can be added in the form of aqueous or alcoholic ammonia or by dissolving the 2,4- di-(chlorosulfonyl)-anilidene in an inert organic solvent and bubbling ammonia gas into the solution.

As the amination reaction may be quite vigorous, it is preferred to add the 2,4-di-(chlorosulfonyl) anilidene (II) to liquid ammonia in a gradual portionwise fashion. The excess ammonia is evaporated leaving a residue which may be triturated with water or dilute acid to neutralize any remaining traces of ammonia.

The so-prepared 3 ,4-dihydro-1,2,4-benzothiadiazine-1,1- dioxides may then be purified by usual methods well known in the art such as crystallization fnom a solvent.

The aniline-2,4-disulfonyl chlorides used in this may be prepared by reacting 3-ch1oroaniline, 3-br0moaniline, 3- fiuoroaniline, and S-trifiuoromethylaniline with chlorosulfonic acid according to procedures well described in the art.

The aldehydic compounds that may be condensed with the aniline-2,4-disulfonyl chloride may be an aldehyde or a derivative convertible thereinto. Representative of suitable aldehydic reactants are: alkanals such as acetaldehyde, propionaldehyde, n-butyraldehyde, iso-butryaldehyde, valeraldehyde, caproaldehyde, and enantheldehyde; halo-alkanals such as chloroacetaldehyde, dichloroacetaldehyde, chloral; alkenals such as acrolein, methacrolein, crotonaldehyde, and 4-pentenal; alkoxyalkanals such as methoxyacetaldehyde, ethoxyacetaldehyde, B-methoxypropionaldehyde and ,B-methoXy-n-butyraldehyde; alkanoylalkanals such as acetoacetaldehyde, propionylacetaldehyde and e-hexanoyl-n-butyraldehyde; aromatic aldehydes such as benzaldehyde, 0, m, and p-tolualdehyde, hexahydrobenzaldehyde, phenylacetaldehyde, hydrocinnamaldehyde, and hydroxy or lower alkoxybenzaldehydes (e.g., salicylaldehyde and anisaldehyde); monocyclic heterocyclic aldehydes such as 2, 3, or 4-pyridyl-aldehyde and pyrrolealdehyde; benzylthioalklaldehydes such as benzylthioacetaldehyde and the acetals and hydrates of the foregoing; vinyl ethers and halo vinyl ethers such as ethyl vinyl ether, and B,B-dichlorovinylethyl ether; and ethers and halo ethers such as ethyl ether and 1,2,2-trichloroethyl ether.

Among the more suitable acid catalysts are strong mineral acid catalysts such as hydrochloric acid and sulfuric acid; and others represented by p-toluenesulfonic acid and trichloroacetic acid.

As indicated above, it is possible to conduct the condensation reaction without a separate solvent, as when an aniline-2,4-disulfonyl chloride is condensed with an aromatic aldehyde, e.g., benzaldehyde; however, a solvent is preferably employed. Solvents suitable for use in this reaction include polyglycol ethers, such as'diethylene glycol dimethyl ether; esters such as ethyl acetate; cyclic ethers such as d-ioxane and tetrahydrofuran; and aromatic hydrocarbons such as benzene and toluene. When water is a by-product of the condensation reaction, it is preferred to use water immiscible solvents capable of forming an azeotropic mixture with water, e.g. benzene, toluene, xylene and the like.

The preparation of these compounds is more fully described in the following examples. It is to be understood, however, that the examples are illustrative of the process, and compounds embraced by this invention and are not to be construed as limiting the invention to the particular compounds or process specifically exemplified.

EXAMPLE 1 3 -d i chloromethyl-6-chl0r0-7-sul famyl-3 ,4-dihydr- 1,2,4-benz0thiadiazine-1,1-di0xide 4 A. S-UHIJORO- (B,fl DICH LOROETHYLIDE'NEAM-INO)- BENZENE-ZA-D'ISUIJFONYL CHLORIDE .To a solution of 10 g. of 5-chloroaniline-2,4-disulfonyl chloride in 250 cc. of benzene are added 5.2 g. of dichloroacetaldehyde and 0.2 g. of p-toluenesulfonic acid, and the resulting mixture is refluxed for 16 hours with continuous azeotropic removal of water. The benzene is removed by evaporation under reduced pressure and the residual product is crystallized from an acetone-water system to give 5-chloro-(B, 8-dichloroethylideneamino)benzene-2,4- disulfonyl chloride as light yellow needles, MP. 153- 154 C.

5 chloro (B,B dichloroethylideneamino) benzene- 2,4-disulfonyl chloride, prepared as in part A above, is gradually added to 30 cc. of liquid ammonia. The excess of liquid ammonia is rapidly evaporated and the residue is immediately acidified with 30 cc. of cold 10% hydrochloric acid, which upon trituration yields a light-colored solid which is collected by filtration, washed with cold water, dried, and crystallized from a methanol-chloroform system to give 3-dichlorornethyl-6-chloro-7-sulfamyl-3,4- dihydro-1,2,4-benzothiadiazine 1,1 dioxide, M.P. 273- 2 74 C.

In a manner similar. to that described in part A of 'Ex ample 1, other anilidene-2, 4disulfonyl chlorides such as the following are prepared: S-chloro-(ethylideneamino)- benzene-2,4-disulfonyl chloride by the reaction of acetaldehyde and S-c'hloroaniline-Z,4-disulfony1 chloride; 5- chloro-(propylideneamino)-benzene-2,4-disulfonyl chloride by the reaction of propionaldehyde with 5-chloronilineQA-disulfonyl chloride. Similarly, by reacting 5- chloroaniline-2,4-disufionyl chloride with n-butyraldehyde, valeraldehyd-e, hexa-hydrobenzalde'hyd-e, p-chloracetaldehyde, chloral, acetaldehyde, ;8(2pyridyl)-propionaldehyde, benzylthioacetaldehyde, there is produced, respectively, the iollowing:

5-chloro-( butylideneamino -'benzene-2,4- disulfonyl chloride,

5-chloropentylideneamino) -benzene-2,4-'disu1fonyl chloride,

5-chloro hexahydrobenzylideneamino) -benzene-2,4- disulfonyl chloride,

5-.ch1orofi-chloroethylideneamino #benZene-ZA-disulfonyl ch-lo-ri-de,

5-chlorofi, 8,;3-trich1-oroethylideneamino) -benzene-2 ,4-

disulfonyl chloride,

5-chloro- (ethylideneamino) -:benzene-2,4-disulfonyl chloride,

S-ch'loro-(5-(2-pyridy1) propylidenearninm) -benzene- 2,4-disu'lfonyl chloride,

5-c-hloro-(benzylthioethylideneamino)-benzene-2,4-disulfonyl chloride.

By the reaction of these compounds with liquid ammonia, as described in part B of Example 1, there is produced Analogously, by reacting =5-trifluoromethyl-aniline-2,4- disulfonyl chloride with dichloroaceta-ldehyde, phenylpropionaldehyde, benzylthioacetaldehyde, there is produccd S-trifluorom ethylfi,,8-dichloroethylidene amino -benzene-2,4-.disulfonyl chloride,

S-trifluoromethyL(-phenylpropylidene amino) -benzene- 2,4-disulfonyl chloride,

S-trifiuoromethyb benzylthioethylideneamino) -benzene- 2,4-disulfonyl chloride, respectively.

These compounds when reacted with liquid ammonia produce, respectively,

3-B,fl-dichlorornethyl-6-trifluoromethyl-7-sulfamyl-3,4-

dihydro-1,2,4-benzothiadiazine-1,l-dioxide,

3-phenethyl 6-trifiuoromethytl-7-sulfamyl-3,4-dihydro- 1,2, 4 benzothia.diazine-1,l-dioxide,

3-benzy1-thion1ethyl-6-trirfluorornethyl-7-sulfamyl-3,4-dihydro-1,2,4 benzothiadiazine-1,'1-dioxide.

EXAMPLE 2 3-dibrom0methyl-6-chloro-7-ts'ulfamyl-3,4-dihydr0- 1 ,2,4-benz0thiadiazine-1,1 dioxide A. -CHLOR0-(5,5-DIBROMOEDHYLIDENEAMINO)- BENZENE2,4-DISU-LEONY'L CHLORIDE To a solution of 10 g. of S-chloroaniline-2,4-dis-ulfonyl chloride in 250 cc. of benzene are added 1-2.7 g. of dibrornoacetal, 0.2 g. of p-toluenesulfonic acid and 0.1 cc. of water, and the resulting mixture is refluxed for 16 hours. The benzene is removed by evaporation under reduced pressure and the residual product is crystallized from an acetone-water system to give 5-chloro-(,6,B-dibrdornoethy lideneamino) benzene 2,4 disulfonyl chlor1 e.

The S-chloro-({3,[3-dibromoethylideneamino) benzene- 2,4-disulfonyl chloride (prepared as in part A above) is gradually added to cc. of liquid ammonia. The excess of liquid ammonia is rapidly evaporated and the residue is immediately acidified with 30 cc. of cold 10% hydrochloric acid, which upon trituration yields a solid which is collected by filtration, washed with cold water, dried, and crystallized from a methanol-chloroform system to give 3-dibrornomethyl-6-chloro-7-sulfamlyl3,4-dihydro 1,2,4- benzothiadiazine-l,l-dioxide.

EXAMPLE 3 3-dichlorom'ethyl-6-chloro-7-sulfamyl-3,4-dihydro- 1,2,4-benz0thiadiazine-1 ,1 -di0xide A. 5-C-HJIJORO- B,BJJFCETLO'ROETHYLIDENEAMINO BENZENE-2,4{UISUIIFONYL CHLORIDE To a solution of 10 g. of S-chloroaniline-2,4-disulfonyl chloride in 250 cc. ofbenzene are added 5.7 g. of dichloro-. acetaldehyde hydrate and 0.2 g. of p-toluenesulfonic acid, and the resulting mixture is refluxed for 16 hours with continuous azeotropic removal of water. The benzene is removed by evaporation under reduced pressure and the residual product is crystallized from an acetone-water system to give S-chloro-([3,5-dichloroethylideneamino)- benzene-2,4-disulfonyl chloride.

S-chloro- 8,;8-dichloroethylideneamino) benzene-2,4- disulfonyl chloride, prepared as in part A above, is gradually added to 30 cc. of liquid ammonia. The excess of liquid ammonia is rapidly evaporated and the residue is immediately acidified with 30 cc. of cold 10% hydrochloric acid, which upon trituration yields a light-colored solid which is collected by filtration, washed with cold water, dried, and crystallized from a methanol-chloroform system to give 3-dichlorometh yl-6-chloro-7-sulfamyl- 3,4-dihydro-1,2,4-benzothiadiaZine-1,l-diox-ide, MP. 273- 274 C.

EXAMPLE 4 3-phenyl-6-chl0r0methyl-7-sulfamyl-3,4-dihydro- 1,2,4-benzothiadiazine-1,1 -dixide -A. 5 CI-DIJO'R'O( BENZYLLDENIEAIMINO)-iBENZENE-2,4- DISU'DFONIYL 'CHIJO'RI'DE A mixture of g. of S-chloroaniline2,4-disulfonyl chloride, 0.2 g. of p-toluenesulfonic acid, and 25 cc. of benzaldehyde is heated at 120 C. for 2 hours. The excess liquids are removed by evaporation under reduced pressure, and the residual product is crystallized from an acetone-water system to give 5-chloro-(benzylideneamino)-benzene-2,4-disulfonyl chloride.

DDHTDROH,2,4-BENZOTHIALDIAZINEJ,l-DIOXIDE S-chloro-(benzylideneamino) benzene 2,4-disulfonyl chloride (prepared as in part A above) is gradually added to 30 cc. of liquid ammonia. The excess liquid ammonia is rapidly evaporated and the residue is immediately acidified with 30 cc. of cold 10% hydrochloric acid, which upon trituration yields a solid which is collected by filtration, washed with cold water, dried, and crystallized from a methanol-chloroform system to give 3-pheny'l-6- chloromethyl-7-sulfamyl-3,4 dihydro 1,2,4 benzothiadiazine-1,1-dioxide.

We claim:

1. A compound of the following formula:

X- N=0H-R ClOzS- SOaCl wherein X is a member of the group consisting of halogen and .trifluoromethyl; and R is a member of the group consisting of alkyl, haloalkyl, benzyl, phenyl, pyridyl, and benzylthioalkyl radicals,

'2. 5 chloro-([3,;3-dichloroethylideneamino)-benzene-2, 4-disulfonyl chloride.

-3. S-trifluoromethyh(,B-phenethylideneamino)-benzene- 2,4-disulfonyl chloride.

4. 5 chloro-(p'henylpropylideneamino)-benzene-2,4-disulfonyl chloride.

5. The process for preparing a 2,4-di-(chlorosulfonyl)- anllidene having the structural formula:

wherein X is a member of the group consisting of halogen and tritluorornethyl; and R is a member of the group consisting of alkyl, haloalkyl, benzyl, phenyl, pyridyl, and benzylthioalkyl radicals; comprising the step of heating together a 5(X)-aniline-2,4-disulfonyl chloride with a reactant of the group consisting of aldehydes having the formula RCHO, and the acetals and hydrates thereof, in the presence of a strong acid catalyst, said catalyst being present in amounts up to about 0.03 mole per mole of said disulfonyl chloride, at a temperature Within the range of at least 40 C. to about the boiling point of the reaction mixture.

'6. The process according to claim 5, wherein the heating step is carried out in an inert solvent.

7. The process according to claim 6, wherein the heating is carried out at about reflux temperature of the reaction mixture.

8. The process for preparing 5-chloro-(fi,,8-dichloroethylideneamino)-'benzene-2,4-disulfonyl chloride comprising the steps of mixing 5-chloroanilne-2,4-disulfonyl chloride with dichloroacetaldehyde in the presence of a strong acid catalyst, said catalyst being present in amounts up to about 0.03 mole per mole of said disulfonyl chloride in an inert solvent at a temperature from about 40 C. to about reflux temperature.

References Cited by the Examiner UNITED STATES PATENTS 1,911,719 5/33 Schweitzer et a1. 260-543 1,939,025 12/33 Schweitzer et a1. 260-543 2,269,450 '1/42 Fitch 260-566 2,684,976 7/54 Glickmana 2,738,347 3/56 Bernstein et a1 260-566 X 2,809,194 10/ 57 Novello 260-243 2,847,473 8/58 Robertson 260-566 2,910,475 10/5'9 N ovello 260-243 2,910,476 1 0/59 Novello 260-543 X 3,095,446 6/63 Margerison et a1. 260-543 LORRAINE A. WEI-NBERGER, Primary Examiner.

, IRVING MARCUS, LEON ZITVER, Examiners. 

1. A COMPOUND OF THE FOLLOWING FORMULA:
 5. THE PROCESS FOR PREPARING A 2,4-DI-(CHLOROSULFONYL)ANILIDENE HAVING THE STRUCTURAL FORMULA: 